New neurons are continuously generated from neural stem cells in two discrete regions of the adult mammalian brain: the subventricular zone of the lateral ventricle and the subgranular zone of the hippocampal dentate gyrus. We have previously shown that adult hippocampal neurogenesis is regulated by interaction of neural stem cells with the local astrocyte population. Adult hippocampal astrocytes provide an environment that instructs neural stem cells to adopt a neuronal fate. Both diffusible and membrane-bound factors derived from hippocampal astrocytes contribute to these effects; however, the identity of these factors and the respective signaling pathways remain unknown. Our preliminary results indicate that hippocampal astrocytes express members of the Wnt family of proteins, including Wnt3, and that Wnt3 enhances the neuronal differentiation of adult neural stem cells. Conversely, blocking of hippocampal astrocyte-derived Wnts decreases the neuronal differentiation of neural stem cells in astrocyte/neural stem cell co-cultures. Furthermore, perturbation of Wnt signaling in vivo decreases the rate of neurogenesis in the adult hippocampus, suggesting that Wnt signaling plays a central role in adult hippocampal neurogenesis. In this proposal we will investigate the role of hippocampal astrocyte-derived Wnts and Wnt signaling in hippocampal neurogenesis in vitro and in vivo. Moreover, we will begin to investigate the functional consequences of perturbed Wnt signaling on hippocampal neurogenesis and hippocampal function. Finally, we will investigate how manipulation of Wnt signaling in other regions of the adult CNS influences the behavior of endogenous NSCs in non-neurogenic regions. These studies will not only lead to a better understanding of the molecular signals controlling the behavior of adult NSCs but will also provide a first insight into the role of Wnt-dependent neurogenesis in hippocampal function. The studies may also ultimately help in the design of therapeutic approaches in CNS disorders that aim at the recruitment of endogenous NSCs for replacement of dying neurons.